Talazoparib fails to extend OS vs. chemotherapy in BRCA-mutated advanced breast cancer
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Talazoparib did not significantly improve OS compared with physician’s choice of chemotherapy for patients with HER2-negative advanced breast cancer with germline BRCA1 or BRCA2 mutations, according to results of the randomized phase 3 EMBRACA trial presented at the virtual American Association for Cancer Research Annual Meeting.
However, extended follow-up continued to show patient-reported outcomes favored talazoparib (Talzenna, Pfizer), and the agent appeared well-tolerated, researchers noted.
“Most patients in the study went on to receive subsequent therapies, which may have confounded the survival analysis,” Jennifer K. Litton, MD, associate professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, said during a presentation. “Talazoparib offers a favorable treatment option for patients with locally advanced or metastatic breast cancer and a germline BRCA1 or BRCA2 mutation.”
The multinational, open-label EMBRACA trial included 431 patients with HER2-negative locally advanced or metastatic breast cancer who harbored germline BRCA mutations.
Researchers randomly assigned 287 patients (median age, 45 years) to talazoparib — a poly(ADP-ribose) polymerase (PARP) inhibitor — dosed at 1 mg once daily. The other 144 patients (median age, 50 years) received physician’s choice of chemotherapy, which included capecitabine, eribulin (Halaven, Eisai), gemcitabine or vinorelbine.
PFS served as the primary endpoint, and OS served as a key secondary endpoint.
Prior results showed talazoparib improved PFS (median, 8.6 months vs. 5.6 months; HR = 0.54; 95% CI, 0.41-0.71) and also improved patient-reported outcomes.
At interim analysis, the HR for OS numerically favored talazoparib but the improvement did not reach statistical significance.
“The toxicity profile of talazoparib was manageable using supportive care and dose modifications,” Litton said. “Importantly, patient-reported outcomes favored talazoparib, and patients who receive talazoparib had significant improvements in terms of delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer-specific symptoms and functions, quality of life and global health.”
At AACR Annual Meeting, Litton reported results of the final OS analysis, as well as updated safety and patient-reported outcome results.
Median follow-up was 44.9 months in the talazoparib group and 36.8 months in the chemotherapy group.
Results showed no significant difference in OS between talazoparib and chemotherapy (median, 19.3 months vs. 19.5 months; HR = 0.85; 95% CI, 0.67-1.07). However, at 48 months, survival probability was higher with talazoparib (HR = 0.19; 95% CI, 0.14-0.25) than chemotherapy (HR = 0.07; 95% CI, 0.02-0.15).
OS results appeared consistent across subgroups, including those based on prior platinum chemotherapy receipt, BRCA status, or triple-negative or hormone receptor-positive status.
A higher percentage of patients assigned chemotherapy received subsequent therapy with a PARP inhibitor (32.6% vs. 4.5%), whereas a higher percentage of patients assigned talazoparib received subsequent platinum-based therapy (46.3% vs. 41.7%).
Interpretation of OS results may have been confounded by subsequent treatment, Litton said, so researchers conducted two sensitivity analyses that accounted for subsequent PARP inhibitor and/or platinum therapy.
Among patients who received either subsequent therapy, median OS was 19.3 months for those initially assigned talazoparib and 17.4 months for those initially assigned chemotherapy (HR = 0.75; 95% CI, 0.5-1.02). Among patients who received subsequent PARP inhibitor therapy only, median OS was 19.3 months for those initially assigned talazoparib and 19.1 months for those initially assigned chemotherapy (HR = 0.82; 95% CI, 0.61-1.04).
“In both sensitivity analyses, according to subsequent PARP and/or platinum, the HR and upper bound of the 95% confidence intervals decreased ... suggesting the primary OS analysis underestimated the treatment benefit of talazoparib,” Litton said.
An exploratory analysis showed patients with longer platinum treatment-free interval prior to study entry — particularly those assigned talazoparib — were more likely to achieve longer survival, Litton added.
The overall safety profile of talazoparib appeared consistent with that observed in the primary analysis, Litton.
Median exposure to treatment was 6.9 months (range, 0.3-61.4) in the talazoparib group and 3.9 months (range, 0.2-36.3) in the chemotherapy group.
A comparable percentage of patients assigned talazoparib and chemotherapy experienced any adverse event (98.6% vs. 97.6%), serious adverse events (35.3% vs. 31%), serious and drug-related adverse events (10.5% vs. 8.7%), and grade 3 or grade 4 serious adverse events (28.3% vs. 27%).
The most common grade 3 or grade 4 adverse events reported in the talazoparib group were hematologic in nature — specifically anemia (40.2%), neutropenia (22.3%) and thrombocytopenia (14.7%) — and were successfully managed by supportive care, including transfusions and dose modifications.
“Of note, one patient [assigned to the chemotherapy group] had been diagnosed with AML at the time of the first analysis,” Litton said. “Now, we report an additional case of AML in a patient who was [randomly assigned] to the talazoparib arm.”
Talazoparib-treated patients were slightly less likely to discontinue treatment due to adverse events (5.9% vs. 8.7%).
The most common nonhematologic adverse events in the talazoparib group were fatigue (51.4% for talazoparib vs. 42.9% for chemotherapy), nausea (49.7% vs. 47.6%) and headache (33.9% vs. 23%).
Litton and colleagues reported statistically significant improvement in estimated overall change from baseline in global health status/quality of life scores for those assigned talazoparib (2.1; 95% CI, 0.1-4.1) and a significant deterioration among patients assigned chemotherapy (–5.7; 95% CI, –10 to –1.4; P for comparison = .001). – by Mark Leiser
Reference:
Litton JK, et al. Abstract CT071. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: Pfizer provided funding for this study. Litton reports grant or research support from, consultant/advisory roles with, speakers bureau roles with, honoraria from or review panel membership with ASCO, AstraZeneca, Ayala Pharmaceuticals, Clinical Care Options, EMD Serono, Genentech, GlaxoSmithKline, MedImmune, Med Learning Group, MedPage Today, Medscape, National Comprehensive Cancer Network, NIH/Physician Data Query, Novartis, Pfizer, Physicians’ Education Resource, Prime Oncology, UpToDate and Zenith Epigenetics. Please see the abstract for all other researchers’ relevant financial disclosures.
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Litton JK, et al. Abstract CT071. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
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