The poly (ADP-ribose) polymerase inhibitor talazoparib did not improve overall survival in women with metastatic HER2-negative breast cancer and mutations in the BRCA1 and BRCA2 genes, according to new results from the phase III EMBRACA trial presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting.¹ This conclusion was somewhat surprising, given that an earlier analysis of EMBRACA showed talazoparib improved progression-free survival and patient-reported outcomes in this group of patients.²

Jennifer K. Litton, MD

“Talazoparib did not improve overall survival. Overall survival is always an important endpoint, but it is also a challenge for patients with metastatic breast cancer, as there are many treatment options. Most of the patients in the trial went on to subsequent therapies, including other PARP inhibitors and platinums, which may have confounded the overall survival analysis,” said Jennifer K. Litton, MD, Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, during her presentation at the AACR meeting.

“The observed safety was consistent with previous reports, and extended follow-up showed continued improvements in patient-reported outcomes with talazoparib. Talazoparib offers a favorable treatment option for patients with locally advanced or metastatic breast cancer and a germline BRCA1 or BRCA2 mutation,” Dr. Litton stated.

“We also found the toxicity [of talazoparib] was manageable using supportive care and dose management. Patients had a significant overall improvement in time to clinically meaningful deterioration in breast cancer–specific symptoms,” she added.

Study Background

EMBRACA is the largest trial of PARP inhibitor monotherapy to date in patients with BRCA-mutated, HER2-negative breast cancer. The primary analysis showed that talazoparib significantly prolonged progression-free survival compared with chemotherapy, with a median of 8.6 months vs 5.6 months, respectively.² On the basis of those results, the U.S. Food and Drug Administration approved talazoparib for patients with germline BRCA mutations in 2018.

Dr. Litton presented secondary endpoint results, including overall survival, based on an intent-to-treat population after 324 deaths occurred. With a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, there were 216 deaths in the talazoparib arm and 108 deaths in the chemotherapy arm. The treatment effect of talazoparib was similar regardless of BRCA status.

EMBRACA Details

The open-label, randomized, phase III EMBRACA trial enrolled patients with locally advanced or metastatic HER2-negative breast cancer with BRCA1 or BRCA2 mutations. The intent-to-treat population included 431 patients who were randomly assigned 2:1 to receive talazoparib or physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine).

Baseline characteristics were generally similar between the two treatment arms. Among all patients, 54% had hormone receptor–positive disease and 46% had triple-negative breast cancer. BRCA1 mutations were present in 45% and BRCA2, in 55%. The talazoparib arm had a higher proportion of patients with worse Eastern Cooperative Oncology Group performance status and of breast cancer that progressed to aggressive disease within 12 months.

No difference in survival was observed between the two groups. This finding was consistent across all prespecified subgroups, irrespective of BRCA status or hormone receptor status.

However, subsequent treatment may have confounded survival results, since almost half of the patients on the talazoparib arm and nearly 60% of patients on the chemotherapy arm went on to further systemic therapy with a PARP inhibitor or platinum agent. Specifically, about one-third of patients in the chemotherapy arm received a subsequent PARP inhibitor, compared with 4.5% in the talazoparib arm. Subsequent platinum therapy was given to about 46% of the talazoparib group and about 42% of the chemotherapy group.

“Patients on the chemotherapy arm who did not get a PARP inhibitor or platinum therapy had a shorter duration of survival than those who did. This is similar in the talazoparib arm. In both sensitivity analyses, primary overall survival adjusting for subsequent treatment with PARP inhibitors and platinum agents suggested the treatment benefit of talazoparib was underestimated,” she told listeners.

“Patients with a longer platinum-free interval prior to study entry were more likely to have longer survival, and this was particularly true for talazoparib-treated patients [median overall survival = 6.9 months, compared with 3.9 months for chemotherapy],” she continued.

Safety Profile

Overall safety was consistent with the primary analysis of ­EMBRACA. The majority of patients reported adverse events. Grade 3 and 4 hematologic adverse events were reported in 56.6% of the talazoparib arm and 38.9% of the chemotherapy arm. Most grade 3 and 4 events reported with talazoparib were hematologic and were successfully managed by supportive care and dose adjustments. Anemia was the most common hematologic event reported with talazoparib (54.9% compared with 19% on chemotherapy). One patient in each arm developed acute myeloid leukemia.

Nonhematologic treatment-emergent adverse events reported with talazoparib included fatigue, nausea, and headache and with chemotherapy, nausea, and fatigue. The incidence of grade 3 and 4 nonhematologic events was approximately 30% in both arms.

“Talazoparib offers a favorable treatment option for patients with locally advanced or metastatic breast cancer and a germline BRCA1 or BRCA2 mutation.”

— Jennifer K. Litton, MD

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“Patient-reported outcomes remain consistent and are improved with talazoparib,” Dr. Litton continued. “Global health quality-of-life scores were significantly improved, whereas they deteriorated with chemotherapy.”

There was a significant delay in the time to clinically meaningful deterioration in quality-of-life scores in the group treated with talazoparib: 26.3 months, compared with 6.7 months in the chemotherapy arm. 

DISCLOSURE: The study was funded by Medivation (acquired by Pfizer in 2016). Dr. Litton has received honoraria from UpToDate; has served in a consulting or advisory role for AstraZeneca, Ayala Pharmaceuticals, Medivation/Pfizer, and Pfizer; has participated in a speakers bureau for Clinical Care Options, Med Learning Group, MedPage Today, Medscape, Physician Education Resource, Prime Oncology, and UpToDate; has received institutional research funding from AstraZeneca, EMD Serono, Genentech, GlaxoSmithKline, Medivation/Pfizer, Novartis, Pfizer, and Zenith Epigenetics; holds patents or other intellectual property from UpToDate; has been reimbursed for travel, accommodations, or other expenses by Clinical Care Options, Med Learning Group, Medscape, and Physician Education Resource.

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 the randomized phase III EMBRACA trial. 2020 AACR Virtual Annual Meeting. Abstract CT071. Presented April 27, 2020.

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 379:753-763, 2018.