This post has been updated to include additional comment from MD Anderson's Jennifer Litton.
NEW YORK – New results from the EMBRACA trial showed that while advanced breast cancer patients with BRCA1 or BRCA2 mutations treated with the PARP inhibitor talazoparib (Pfizer's Talzenna) lived on average as long as those on chemotherapy, talazoparib-treated patients reported a better quality of life.
However, oncologists may continue to prescribe the drug for advanced, BRCA1/2-mutated breast cancer patients based on the quality of life parameters reported in this trial. Additionally, more detailed biomarker analysis within EMBRACA supported the continued use of BRCA1/2 mutation status to identify best responders.
Previous results from the EMBRACA trial, published in 2018 in the New England Journal of Medicine, indicated that patients treated with talazoparib had longer progression-free survival compared to patients treated with their physician's choice of chemotherapy. Based on these results, that same year the US Food and Drug Administration approved talazoparib alongside Myriad Genetics' BRACAnalysis CDx to identify individuals who have BRCA1/2 mutations and who are likely to respond well to the drug.
At the American Association for Cancer Research's Virtual Annual Meeting this week, researchers from the University of Texas MD Anderson Cancer Center presented additional data from the trial, including an overall survival analysis and an analysis of whether a loss of BRCA mutation heterozygosity in the tumor affects clinical benefit.
"PARP inhibitors have been a major advance in BRCA1 and 2 mutation-associated tumors," noted the University of Pennsylvania's Susan Domchek in her discussion of the new results at the meeting.
The EMBRACA trial enrolled 431 patients with HER2-negative, locally advanced or metastatic breast cancer who had inherited BRCA1 or BRCA2 gene mutations. The patients were randomized to receive either talazoparib or their physician's choice of single-agent chemotherapies like capecitabine, eribulin, gemcitabine, or vinorelbine.
After a respective median follow up of 44.9 months and 36.8 months for talazoparib and chemotherapy, respectively, 216 patients in the talazoparib group and 108 patients in the chemotherapy group died, Jennifer Litton, a breast medical oncologist at MD Anderson, reported in her AACR presentation. The talazoparib group had a median overall survival of 19.3 months and the chemotherapy group had a median overall survival of 19.5 months, a difference that was not statistically significant.
This, Domchek said in her discussion, is similar to results she and her colleagues published last year in the Annals of Oncology from the OlympiAD study. They found no statistically significant improvement in overall survival among HER2-negative metastatic breast cancer patients with germline BRCA mutations treated with the PARP inhibitor olaparib (AstraZeneca's Lynparza) as compared to chemotherapy.
In the EMBRACA trial, Litton noted, though, that about half the patients in the talazoparib group and nearly 60 percent of patients in the chemotherapy group underwent platinum chemotherapy or PARP inhibitor treatment upon progression, which may have confounded their overall survival results. PARP inhibitors, she noted, became increasingly available commercially or through clinical trials during the course of the study, and a third of the chemotherapy group was eventually treated with a PARP inhibitor. Only a small portion of talazoparib-treated patients, 4.5 percent, received additional PARP inhibitor therapy; 46 percent were subsequently treated with platinum chemotherapy.
Sensitivity analyses to determine the effects of any subsequent PARP inhibitor or platinum therapy indicated that the overall survival analysis may have underestimated the treatment benefit of talazoparib. Neither analysis, though, reached statistical significance.
Still, patients in the talazoparib arm reported better quality of life scores. They reported a significantly longer time-to-health deterioration, 26.3 months, than patients in the chemotherapy arm, who reported their health deteriorating in 6.7 months.
Oncologists will factor this into their risk/benefit assessments of the drug. "PARP inhibitors for patients with germline BRCA mutations remain an excellent option for these patients, given the ease of administration, the improvement of quality of life, the measured improvement in progression free survival," Litton said in an interview. "Disappointingly, this did not show a statistically significant overall survival [but] given treatment options for metastatic cancer, I think this remains an excellent option."
EMBRACA trial researchers also examined whether tumor genomics influenced talazoparib response.
To be eligible for the EMBRACA trial, patients had to undergo germline screening for BRCA1 or BRCA2 gene mutations via Myriad Genetics' BRACAnalysis CDx test. And in an analysis presented by Lida Mina, the associate director of breast programs at Banner MD Anderson, patients' tumor samples were also analyzed using Foundation Medicine's FoundationOne CDx next-generation sequencing panel to look for SNVs, indels, or rearrangements known or suspected to be pathogenic, as well as any loss-of-heterozygosity and BRCA zygosity.
In 2015, Myriad Genetics and BioMarin Pharmaceuticals — which developed talazoparib before selling it to Medivation, which was acquired by Pfizer — entered into a collaboration to use Myriad's myChoice HRD test, which detects loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions, to identify metastatic breast, ovarian, and patients who might benefit from treatment with talazoparib.
For EMBRACA, the researchers analyzed tumor tissue from 308 patients, 96 percent of whom had at least one tumor BRCA mutation. There was a high, 95 percent concordance rate between germline and tumor BRCA mutations. Discordance was only seen in 14 patients and, Mina said, which could be due to differences in classifying variants between the two vendors.
A total of 236 tumor samples underwent zygosity evaluation to find 83 percent had BRCA loss of heterozygosity in which they retained the mutant BRCA allele. Within the talazoparib arm, Mina and her colleagues compared the 122 patients with and the 27 patients without that loss of heterozygosity to find they had similar progression-free survivals.
There was also no association between BRCA loss of heterozygosity and clinical benefit in either the talazoparib or chemotherapy arms.
When broken down by breast cancer subtype, genome loss of heterozygosity was more common among patients with triple-negative breast cancer who had increased clinical benefit to talazoparib compared to those with no clinical benefit, Mina noted.
This confirms, Mina added, that germline BRCA status should continue to be used to identify patients for whom this treatment might work. "Germline BRCA mutational status is an appropriate and potentially optimal biomarker for the identification of patients with HER2-negative advanced breast cancer who may benefit from treatment with talazoparib," she said.
Domchek noted that while allele-specific loss of heterozygosity is common among tumors in patients with germline BRCA1 or BRCA2 mutations, there are still patients who retain that heterozygosity and their tumors can look quite different. Still, she added, "At this time, germline BRCA1 and 2 pathogenic variants are the best predictors of PARP inhibitor sensitivity in breast cancer."