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Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
FROM AACR 2020