Results from the largest-ever study to evaluate a PARP inhibitor as a treatment for inpatients with advanced HER-2 negative breast and germline BRCA1/2 genes, may change the way physicians treat patients with the disease, for which there currently is no standard of care.
In the open-label, phase III EMBRACA trial led by Jennifer Litton, MD, Associate Professor, Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, the PARP inhibitor talazoparib extended progression-free survival (PFS) over chemotherapy and improved quality of life for patients.
The results were presented last December at the 2017 San Antonio Breast Cancer Symposium (SABCS) by Litton, who along with the co-authors of the study, is being recognized for the groundbreaking research with a 2018 Excellence in Oncology Award from Oncology Times.
Talazoparib “is a highly potent, dual-mechanism PARP inhibitor that inhibits the PARP enzyme and effectively traps PARP on single-stranded DNA breaks, preventing DNA damage repair and causing cell death in BRCA1/2-mutated cells,” Litton explained in the abstract for her SABCS presentation (J Clin Oncol 2018;36(suppl; abstr 508)).
The international randomized trial enrolled 431 patients with 287 receiving talazoparib and 144 undergoing physician's choice of single-agent therapy (PCT), which was either capecitabine, eribulin, gemcitabine, or vinorelbine. Patients were randomized based on the number of prior lines of chemotherapy, hormone receptor status, and history of central nervous system metastases to either talazoparib or PCT.
The primary endpoint for the EMBRACA study was PFS, while secondary endpoints were overall survival, overall response rate, and safety. Exploratory endpoints included duration of response and quality of life.
With a follow-up of 11.2 months, the median PFS was 8.6 months for patients receiving talazoparib, compared to 5.6 months for patients receiving PCT, which is a statistically significant improvement, the researchers noted. Patient-reported global health status and quality-of-life measures included in the study also showed overall improvement from baseline, as well as a delay in the time to clinically meaningful deterioration in patients receiving the treatment.
Patients receiving talazoparib were nearly 46 percent less likely to experience disease progression than those patients who received PCT. The overall response rate was 62.6 percent on the talazoparib arm, compared with just 27.2 percent on PCT. There were a total of 12 complete responses in the trial as well, all in the talazoparib arm. Additionally, patient-reported quality-of-life measures revealed a prolonged time to deterioration of overall health (24.3 months) for the talazoparib arm, compared to 6.3 months for the PCT arm.
The most common adverse event with talazoparib is anemia, for which two patients in the EMBRACA trial discontinued talazoparib. Neutropenia was also a common adverse event with talazoparib, but the rate among the patients was very low (.03%). The common non-hematological toxicities included fatigue, nausea, alopecia, and headaches, the majority being grade 1 or 2.
However, overall, talazoparib was generally well-tolerated and improved patient-reported global health status, according to the researchers. Considering all of the data, they concluded that talazoparib met its primary endpoint with the increase in PFS compared to PCT.
A History of Firsts
Recently, Litton and colleagues presented a separate pilot study of talazoparib without any prior chemotherapy that had a pathological complete response rate of 53 percent. The study also revealed a median 88 percent decrease in tumor size in all 13 patients who took talazoparib for 2 months. The rapid and impressive results quickly led to the modification of the feasibility study into a phase II trial, which is currently underway.
Previous studies showed the promise of the PARP inhibitor in treating breast cancer. In a phase I trial of multiple tumor types, a 1 mg/day continuous daily dosing schedule was established with talazoparib. The phase II ABRAZO trial showed promising efficacy and safety in breast cancer patients with germline BRCA1/2 mutations with either multiple prior lines of chemotherapy or prior platinum therapy.
In an interview with Oncology Times, Litton said the impressive results of these previous studies were among the impetuses for investigating talazoparib in the EMBRACA study. “I have been interested in talazoparib for many years and have participated in previous studies, both with talazoparib and other PARP inhibitors. I think these are an exciting group of compounds, and we still have much to learn on how to expand their use to help more cancer patients,” she noted.
What, if anything, surprised her about the results of the EMBRACA study? “In earlier phase studies with talazoparib, we had seen the rapid response results, so that was not necessarily a surprise from EMBRACA,” Litton stated. “What was surprising was seeing similar time to effect from a single targeted therapy in addition to quality-of-life improvements, which declined for patients on chemotherapy. That is what I saw in my patients at MD Anderson as well.”
Like any major research findings, it is possible for others looking at the study data to arrive at or even jump to incorrect conclusions. “At this point, neither EMBRACA nor the Olympiad study can tell us how to position treatment with PARP inhibitors either before or after platinum chemotherapies, or if we should consider the use of PARP inhibitors after patients with breast cancer develop resistance to platinum-based therapies. Further studies will need to be done to address those questions,” Litton explained.
In terms of the clinical implications, Litton noted that “the development of PARP inhibitors in treating breast cancer was delayed due to the promising phase II results with iniparib, which were followed by a negative phase III study. Iniparib turned out not to inhibit PARP. However, we now have two phase III trials demonstrating their efficacy and safety. In my opinion, PARP inhibitors now have a solid role in treating breast cancer patients with germline BRCA mutations.”
Still, further research is needed, because “even though talazoparib did have improved benefit over the chemotherapies chosen in this study, most patients will develop resistance and progress,” Litton said. “There is a lot of work going on right now, investigating promising combination therapies, which will not only expand PARP inhibitors to other patient groups that may benefit, but also to combine PARP inhibitors with immunotherapy to prolong the duration of response. I am looking forward to the results of multiple ongoing combination studies with PARP inhibitors in breast cancer.”
Chuck Holt is a contributing writer.