Novel BSI-201 Targeted Therapy Holds Promise for Patients with Metastatic Triple-negative Breast Cancer

Novel BSI-201 Targeted Therapy Holds Promise for Patients with Metastatic Triple-negative Breast Cancer

Treatment with BSI-201, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor, in combination with gemcitabine/carboplatin, prolonged both progression-free and overall survival for patients with metastatic triple-negative breast cancer. Joyce A. O’Shaughnessy, MD, of Baylor-Sammons Cancer Center, presented the results of a randomized multicenter phase II trial on behalf of the U.S. Oncology investigators during the Plenary Session on Sunday (Abstract 3).

Based on in vitro evidence of synergy between BSI-201 and both gemcitabine and carboplatin, and gene expression studies demonstrating that PARP-1 is upregulated in triple-negative breast tumors, 62 patients were randomly assigned to gemcitabine/carboplatin and 61 patients to gemcitabine/carboplatin plus intravenous BSI-201 in 3-week cycles. Patients were restaged every two cycles. Primary endpoints were clinical benefit rate (objective response plus stable disease for at least 6 months) and safety; secondary endpoints were overall response rate, progression-free survival, and overall survival.

Demographics and tumor characteristics were evenly distributed between the two groups. Tumors from 50 of the patients were submitted to gene expression profiling, and PARP-1 was significantly upregulated in the majority of them (p < 0.0001). Hematologic and nonhematologic toxicities (nausea, vomiting, fatigue, neuropathy, and diarrhea) did not differ between the two groups, nor were there any substantial differences between the two groups with regard to gemcitabine/carboplatin dose reductions. The mean number of cycles delivered in the gemcitabine/carboplatin group was 4.5 and 6.9 in the BSI-201 plus gemcitabine/carboplatin group.

BSI-201 plus gemcitabine/carboplatin improved the clinical benefit rate (62% vs. 21%, p = 0.0002), objective response rate (48% vs. 16%, p = 0.002), median progression-free survival (6.9 months vs. 3.3 months, HR = 0.342, p < 0.0001), and median overall survival (9.2 months vs. 5.7 months, HR = 0.348, p = 0.0005) compared with gemcitabine/carboplatin alone (Fig. 1).

The promising safety and efficacy results have prompted the initiation of a phase III study that should begin enrollment of patients with metastatic triple-negative breast cancer in late June 2009. The primary endpoints will be progression-free and overall survival rates; secondary endpoints will be overall response rates and safety/tolerability.

Triple-negative breast cancers lack both estrogen and progesterone receptors and HER2 is not overexpressed. They also share certain molecular and pathologic features with BRCA1/BRCA2-related breast cancers. Dr. O’Shaughnessy noted that these tumors are aggressive, metastasizing to the lungs and brain. In addition, about 30% of patients develop metastatic disease, with a median survival of 13 months. Currently available therapies for metastatic triple-negative breast cancer are limited.

Before Dr. O’Shaughnessy’s presentation, Merrill J. Egorin, MD, of the University of Pittsburgh Cancer Institute, provided an overview of the intracellular functions of the 17-member PARP superfamily, in an effort to educate clinicians about the basic science surrounding these molecules. His lecture focused on PARP-1 and PARP-2, both of which are activated as a result of DNA damage. In normal tissue, BRCA1/BRCA2 and PARP-1 are involved in DNA damage repair; however, tumor cells with BRCA1/BRCA2 gene mutations are dependent on PARP for repair of DNA damage. Thus, PARP inhibition selectively kills BRCA1 or BRCA2-deficient cells. The proposed mechanism of action is that accumulated single-strand DNA breaks are converted to double-strand breaks during DNA replication, and as a result, replication forks collapse. Dr. Egorin noted that PARP-1 and PARP-2 are involved in DNA repair, but they also play a role in the organization of chromatin domains, modulation of transcription, and control of cell division.

As well as selectively killing cells with BRCA1/BRCA2 mutations, PARP inhibitors also enhance the antiproliferative activity of DNA-damaging agents, including DNA-methylating drugs (such as temozolomide), topoisomerase I inhibitors (including irinotecan, topotecan, and camptothecin), and radiation. Although PARP-1 inhibitors may prove to be a valuable addition to the limited therapies available for triple-negative breast cancer, many questions remain regarding dose and frequency, relation of the compounds to either pharmacokinetics or pharmacodynamics, the duration of compound activity, and mode of administration.

Questions specific to the role of cytotoxic agents used in conjunction with PARP inhibitors also exist. Dosing relationships, timing of administration, and duration of each therapy should be explored. The role of PARP inhibitors as preventive agents for women with BRCA mutations also requires further study.

Because PARP-1 is involved in many cellular processes, Dr. Egorin predicted a quickly expanding research program for inhibitors of these important molecules.