Pfizer announced that the Phase 3 EMBRACA trial in patients with germline (inherited) BRCA1/2-positive (gBRCA+) locally advanced and/or metastatic breast cancer (MBC) demonstrated superior progression-free survival (PFS) in patients treated with talazoparib, compared to patients who received physician’s choice standard of care chemotherapy. Median PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 5.6 months (95% CI: 4.2, 6.7) for those treated with chemotherapy [HR: 0.54 (95% CI: 0.41, 0.71), p<0.0001]. This represents a 46% reduction in the risk of disease progression. In addition, the proportion of patients achieving a complete or partial response (objective response rate) in the talazoparib group was more than twice that of the control arm (62.6% for talazoparib vs. 27.2% for chemotherapy [OR: 4.99 (95% CI: 2.9-8.8), p<0.0001]). Talazoparib is an investigational, oral, dual-mechanism poly ADP ribose polymerase (PARP) inhibitor that is taken once daily.
“Patients with germline BRCA-positive breast cancer are typically diagnosed at a younger age than those with nonhereditary breast cancer, and there are no therapies specifically approved for them outside of current standard of care therapies,” said Jennifer Litton, MD, lead investigator and associate professor in the breast medical oncology department of The University of Texas MD Anderson Cancer Center. “EMBRACA supports the potential of talazoparib to give these patients additional time without disease progression, compared to chemotherapy.”
Pfizer will be discussing these data from EMBRACA, the largest Phase 3 trial performed to date of a PARP inhibitor in patients with gBRCA+ MBC, with worldwide health authorities. There are currently limited treatment options for patients with this molecular subtype.
The results of the EMBRACA trial also showed that the PFS benefit with talazoparib was consistent across prespecified subgroups, including hormone receptor (HR) status (triple negative [TNBC] or hormone receptor-positive [HR+]), BRCA mutation (1 or 2), prior chemotherapy (whether patients had none or up to three chemotherapies before talazoparib), and history of central nervous system (CNS) metastases. There also was a statistically significant delay in the time to clinically meaningful deterioration in global health status/quality of life with talazoparib versus chemotherapy (HR 0.38 [95% CI 0.26-0.55], p<0.0001), as measured by the EORTC QLQ-C30, a cancer-specific, patient-reported quality of life questionnaire.
Adverse events (AEs) observed with talazoparib were consistent with findings from previous trials. The most common AEs observed with talazoparib (any grade in at least 15% of patients) were anemia (52.8%), fatigue (50.3%), nausea (48.6%), neutropenia (34.6%), headache (32.5%), thrombocytopenia (26.9%), alopecia (25.2%), vomiting (24.8%), diarrhea (22%), constipation (22%), decreased appetite (21.3%), back pain (21%) and dyspnea (17.5%). The incidence of serious AEs was 31.8% in the talazoparib arm and 29.4% in the chemotherapy arm. Discontinuations due to AEs occurred in 7.7% of patients in the talazoparib arm and 9.5% of patients in the chemotherapy arm.
EMBRACA is a global Phase 3, open-label, randomized, parallel, 2-arm trial of talazoparib versus protocol-specific physician’s choice of standard single-agent chemotherapy (PCT [capecitabine, eribulin, gemcitabine or vinorelbine]) in gBRCA+ patients who may have received up to three prior cytotoxic chemotherapy regimens for locally advanced and/or metastatic breast cancer. Patients enrolled had a diagnosis of TNBC or HR+/HER2-negative breast cancer. The trial randomized (2:1) 431 patients to receive talazoparib (1.0 mg) once daily or PCT.
BRCA1 and BRCA2 are human genes that produce proteins involved in DNA repair. When either of these genes is altered or mutated, DNA repair may not progress correctly. This can lead to the development of certain types of cancer such as breast cancer. BRCA mutations can be hereditary (germline) or occur spontaneously (sporadic). Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers. Up to 65 percent of women who inherit a BRCA mutation will develop breast cancer by age 70. Epidemiologic studies indicate that individuals with gBRCA+ status are diagnosed with breast cancer at a median age of 40-45, which is approximately 20 years younger than the overall breast cancer population.
Talazoparib is an investigational anti-cancer compound called a PARP (poly ADP ribose polymerase) inhibitor. Preclinical studies suggest that talazoparib is highly potent and has a dual mechanism of action, with the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. Talazoparib is currently being evaluated in advanced gBRCA+ breast cancer as well as other cancer types with deficiencies in DNA damage repair (DDR). It is also being studied in DDR-deficient prostate cancer and in combination with immunotherapy in various tumor types. Talazoparib has not been approved by any regulatory authorities for the treatment of any disease.