- Research & Development
Talazoparib, an orally available poly-ADP ribose polymerase, or PARP, inhibitor, is currently in a Phase 3 clinical trial for the treatment of patients with gBRCA mutated breast cancer (i.e., advanced breast cancer in patients whose BRCA genes contain germline mutations). In addition, we are targeting a number of other solid tumor indications in which to investigate talazoparib, including breast (beyond gBRCA mutations), prostate, small cell lung, and ovarian cancers.
PARP is a family of proteins involved in a wide range of cellular functions including deoxyribonucleic acid, or DNA, transcription, DNA damage response, genomic stability maintenance, cell cycle regulation, and cell death. One well-studied area of PARP activity relates to DNA repair. Since DNA is the vehicle by which fundamental information is passed on when a cell divides, it is critical to the viability of cells and human health that DNA damage can be repaired. If a cell's DNA damage repair system is impaired, the cell will die.
DNA can be damaged as a result of environmental exposure or agents, or through errors introduced during replication. Cells have a number of different mechanisms to repair damaged DNA. PARPs aid in repair by binding to single-strand breaks in DNA and recruiting additional repair proteins to the site of damage, a process called base excision repair. PARP inhibitors are thought to block this activity, thus preventing the repair of DNA. PARP inhibitors exert a cytotoxic effect by two mechanisms: (a) catalytic inhibition of PARP enzyme activity and (b) PARP trapping.
A single-stranded DNA break signals PARP protein to attach to DNA, a critical step in DNA repair. Inhibition of PARP's catalytic activity impairs the recruitment of additional DNA repair proteins critical for base excision repair and single stranded breaks can become double stranded breaks which require homologous recombination for repair. Cells harboring mutations or deficiencies in homologous recombination (e.g., cells with BRCA1/2 mutations), are particularly susceptible to the cytotoxic effects of PARP inhibitors as these cells tend to accumulate double strand breaks that are inaccurately repaired by alternative pathways.
Another potentially important mechanism of action of talazoparib is the phenomenon called PARP trapping. Talazoparib is thought to trap the PARP molecule on the DNA creating a large protein moiety that interferes with the cell's ability to replicate its DNA thereby causing cell death.
DNA damaging therapies such as radiation and chemotherapy (alkylating agents like temozolomide) modify DNA and initiate PARP-dependent repair processes including base excision repair. Single strand breaks resulting from these therapies create additional sites for PARP to potentially be trapped by talazoparib, which may increase its cytotoxicity. In 2015 in the U.S. alone, approximately 500,000 patients received DNA damaging radiation therapy, while more than 500,000 received DNA damaging chemotherapy. As single-stranded breaks are potential sites for PARP trapping, it is theorized that talazoparib in combination with these DNA damaging agents may have broad activity beyond tumors harboring BRCA1/2 mutations which represent only a small portion of the total oncology market.
The Phase 3 EMBRACA trial is an open-label, 2:1 randomized, parallel, two-arm study of talazoparib as compared to the protocol specified physicians' choice of chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in gBRCA-mutated locally advanced and/or metastatic breast cancer patients who have received prior chemotherapy for their metastatic disease. The study is enrolling up to 430 patients. The primary objective of the study is to compare PFS of patients treated with talazoparib as a monotherapy relative to those treated with protocol-specified physicians' choice. Learn more about the EMBRACA clinical trial.