“PARP inhibitors are a major advance in the treatment of BRCA1- and BRCA2-mutated tumors, including prostate, breast, ovarian, and pancreatic cancers,” said discussant Susan Domchek, MD, Director of the Basser Center for BRCA at Penn Medicine’s Abramson Cancer Center in Philadelphia. Nevertheless, key questions about these agents remain about the clinical predictors of acquired resistance, whether PARP inhibitors should be first-line therapy, whether prior platinum exposure impacts response, and whether earlier treatment might be more effective.
Susan Domchek, MD
No difference in survival was seen in EMBRACA between talazoparib and physician’s choice of chemotherapy. Also, there was no difference in outcomes for those with BRCA2 vs BRCA1 mutations. Although there is no clear signal, survival may be better in patients who have had no prior chemotherapy, she suggested, and subsequent therapy may confound overall survival results.
“Some studies suggest earlier administration of a PARP inhibitor may be better and may avoid acquired resistance,” Dr. Domchek continued. “At this time, germline BRCA1 and BRCA2 variants are the best predictors of PARP inhibitor sensitivity in breast cancer. Homologous repair–deficiency scores and loss of heterozygosity scores do not seem to add much in patients with known germline BRCA1 and BRCA2 mutations.”
Another Perspective
Aditya Bardia, MD, MPH
Despite the failure to improve overall survival, talazoparib has many benefits that support its use, according to Aditya Bardia, MD, MPH, of Massachusetts General Hospital, Boston.
Dr. Bardia told The ASCO Post: “The EMBRACA trial is a landmark study demonstrating that patients with metastatic breast cancer and germline BRCA mutation who received talazoparib had longer progression-free survival than standard chemotherapy. The findings led to the approval of talazoparib in October 2018. At the 2020 AACR meeting, the authors provided an update on the overall survival results and reported no difference in overall survival between the arms, similar to what was reported with olaparib in the Olympiad trial.”
He continued: “Although overall survival is an important benchmark in the metastatic setting, several factors need to be carefully considered in interpreting the results. First, the posttrial treatments could have an impact on overall survival. For example, in the EMBRACA study, approximately one-third of patients in the chemotherapy arm received a subsequent PARP inhibitor, compared with just 4.5% of patients who received talazoparib. Second, many of the trials in the metastatic setting are powered for the primary objective, progression-free survival, and might not be adequately powered for the secondary objective, overall survival. Third, it is also possible that disease progression on talazoparib confers cross-resistance to subsequent therapies, particularly platinums, which could blunt the difference in overall survival between the arms.”
Dr. Bardia concluded: “Further research is needed to better understand drivers of therapeutic resistance. Overall, talazoparib remains an important drug in the therapeutic armamentarium for patients with metastatic breast cancer and germline BRCA mutation.”
DISCLOSURE: Dr. Domchek has received honoraria from AstraZeneca, Bristol-Myers Squibb, and Clovis Oncology; and has received institutional research funding from AstraZeneca and Clovis Oncology. Dr. Bardia has served in a consulting or advisory role for Biotheranostics, Genentech, Immunomedics, Merck, Novartis, Pfizer, Puma Biotechnology, AstraZeneca/Daiichi, Eli Lilly, Foundation Medicine, Phillips, Radius Pharma, Sanofi, and Spectrum Pharmaceuticals; has served in an institutional consulting or advisory role for Genentech/Roche, Immunomedics, Innocrin Pharma, Novartis, Pfizer, and Radius Health; and has received research funding from Biotheranostics.
