Targeted therapies forge ahead in multiple breast cancer subtypes

PARP inhibitors make a dent in BRCA1/2-mutated cancers

The most renowned breast cancer genes, BRCA1 and BRCA2 are present in about 5%-10% of all breast cancers. They play a central role in the homologous recombination pathway that fixes double-strand breaks in the DNA. Genome sequencing studies have revealed that the presence of the BRCA1/2 genes and other DNA repair defects is highest among patients with the basal-like subtype of breast cancer, in particular those who have triple-negative disease.^34,35

This type of breast cancer has proved stubbornly resistant to efforts to improve patient outcomes with targeted therapies. BRCA1/2 mutations and other DNA repair defects that confer a so-called BRCAness phenotype, render tumor cells dependent on other pathways for DNA repair and there has been considerable interest in therapeutically exploiting this through the development of inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme, which is involved in the repair of single-strand breaks in the DNA. The double damage to DNA repair mechanisms through PARP inhibition in patients with BRCA1/2-mutant tumors proves overwhelming to cancerous cells.

Despite more than a decade of investigation in breast cancer, PARP inhibitors have yet to yield any FDA-approved treatment options. That may be set to change imminently, following the success of olaparib (Table 3). In the first randomized phase 3 trial of a PARP inhibitor in breast cancer (OlympiAD), olaparib was compared with standard chemotherapy in patients with BRCA1/2-mutated MBC who had received up to 2 previous lines of chemotherapy. Olaparib reduced the risk of disease progression by 42% compared with standard chemotherapy and was well tolerated.³⁶

The novel PARP inhibitor talazoparib, which is the most potent to date, is also demonstrating significant efficacy in clinical trials. The results of the phase 2 ABRAZO trial were presented at the ASCO annual meeting. Two cohorts were treated; the first included 49 patients who had responded to their last platinum-containing regimen for metastatic disease and progressed more than 8 weeks after last platinum dose and the other included 35 patients previously treated with 3 or more nonplatinum regimens for metastatic disease. ORR was 28% across the 2 cohorts; 23% and 33% in BRCA1- and BRCA2-mutant carriers, respectively; and 26% in patients with triple-negative breast cancer.³⁷ PARP inhibition is not faring so well in early-stage triple-negative disease; a phase 3 trial of veliparib in combination with chemotherapy did not meet its primary endpoint.³⁸